Macrolides have a range of physiological activities. The majority of macrolides have an antimicrobial effect as part of their therapeutic mode of action. The macrolides are not only classified in terms of activity but also based on structure. Erythromycin, the original naturally occurring macrolide, has a 14-membered macrolactone as a backbone. The 12-, 13-, 15- and 16-membered macrolides are mostly modified derivatives of erythromycin as well as the closely related ketolides, which are broad spectrum antimicrobials.
Many macrolides exhibit a range of disease modifying activities in various diseases of seemingly unrelated aetiology. In addition to antimicrobial activity, some macrolides have been proposed to possess alternative “non-antimicrobial” effects. Some of those effects have been proposed to manifest themselves in a disease modifying mode of action in humans that is primarily anti-inflammatory or immunomodulatory (Kanoh, S. and Rubin B. K., Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications, Clinical Microbiology Reviews, 2010, 23(3), 590-615). The term “Immunolides” has been used to describe macrolide compounds that have selective immunomodulatory effects (see Fecik et al., Current Opinion in Drug Discovery and Development, 2005, 8(6), 741-747).
In at least two double blinded clinical trials azithomycin (“Azm”) has been shown to reduce the hospitalisation rate and disease related exacerbations by 30% in patients with COPD (see Uzun et al., Lancet Respiratory Medicine, 2014, 2(5), 361-368 and Albert et al., New England Journal of Medicine, 2011, 365(8), 689-698). Azm has also been shown to increase host defence against P. aeruginosa as well as increasing transepithelial resistance (“TER”) in epithelial cells in vitro ALI culture and increases cellular processing of tight junctions. Erythromycin and penicillin have been found not to exhibit similar effects. (see Asgrimsson V et al (2006) Novel effects of azithromycin on tight junction proteins in human airway epithelia, Antimicrob Agents Chemother, 50: 1805-1812 and Halldorsson S et al. (2010) Azithromycin Maintains Airway Epithelial Integrity During Pseudomonas aeruginosa Infection. Am J Respir Cell Mol Biol. 2010, 42(1),62-68.).
TER is also known as TEER (“transepithelial electrical resistance”), and it is a measure of the electrical impendence of a cell layer. It is used as an indicator of formed and functional tight junctions, see, for example, Rezaee F and Georas S N, 2014, Am J Respir Cell Mol Biol, 857-869. Increased TER is a parameter of good barrier properties and is associated with healthy polarised epithelial tissue whilst diseased or poorly-effective epithelial tissue is associated with poorer barrier function (see, for example, Marchiando et al., Annu. Rev. Pathol. Mech. Dis., 2010, 5, 119-144), and higher permeability, and hence higher permeability.
Over-use of antibiotics is one of the causes of the rise of antibiotic-resistant strains of bacteria. The use of macrolides in the treatment of conditions other than bacterial infections has thus been limited by the need to avoid the unnecessary widespread use of antibiotic compounds. There is thus a clinical need for macrolide compounds with clinically useful immunomodulatory activity but sufficiently low antimicrobial activity not to constitute a resistance-promotion hazard. Despite the significant interest in the development of such immunolides, suitable compounds have not yet been developed. Certain compounds are described in WO2014/166503 as having good non-antibiotic properties but reduced antimicrobial activity. In practice the compounds described therein do not have sufficient activity to be clinically useful.
Some limited numbers of derivatives of azithromycin are known, for example from patent publications WO2006/087644, WO2004/005310, WO2004/139821, WO03/070174 and CN1837225.